Summary of Work: Mononamine Oxidase A and Serotonin Transporter Gene Polymorphisms interact to affect a personality profile associated with resilience, mood and behavior. Senior PSCS investigators are committed to searching for the molecular genetic bases of fundamental personality dimensions. Personality styles or patterns because they summarize many traits in single label are not only conceptually convenient but they might better phenotypes for genetic linkage and association studies. We recently investigated one such personality pattern derived from the Five-Factor Model of Personality involving combinations of Neuroticism (N) and Conscientiousness (C) Genes involved in the regulation of serotonin function have been logical candidates to identify genes linked to personality dimensions associated with mental and physical illness. Much attention has focused on a 44bp insertion/deletion polymorphism of the serotonin transporter gene promoter (5HTTLPR) and an upstream VNTR polymorphism of the MAOA gene promoter (MAOA-uVNTR). The 5HTTLPR long (l) allele and the MAOA-uVNTR 3.5/4 repeats alleles have been reported to be more transcriptionally efficient than the 5HTTLPR short (s) allele and the MAOA-uVNTR 2/3/5 repeats alleles, respectively. The MAOA-uVNTR 2/3/5 repeats alleles are associated with increased violent behavior in men who had been abused in childhood (ref), and the 5HTTLPR s allele is associated with increased depression in adults who experienced high levels of life stress or childhood abuse. To extend and expand upon these findings of gene-environment interactions involving these two genes, we have evaluated the interaction between them as it affects personality profiles on the NEO-PI-R in a sample of 153 healthy normal volunteers, stratified to provide approximately equal numbers of men and women and blacks and whites. We found significant 5HTTLPR (l/l vs. l/s, s/s) X MAOA-uVNTR (3.5/4 vs. 2/3/5 repeats) interactions for the Neuroticism domain (N, P=0.005) and facets of Anxiety (N1, P=0.008), Depression (N3, P=0.02), Impulsiveness (N5, P=0.04), and Vulnerability (N6, P=0.006); and for the Conscientiousness domain (C, P=0.04) and facets of Competence (C1, P=0.04), Dutifulness (C3, P=0.06), Self-Discipline (C5, P=0.04), and Deliberation (C6, P=0.07). In subjects with the more efficient 3.5/4 MAOA-uVNTR alleles the 5HTTLPR l/s and s/s genotypes had N and C domain/facet scores that were similar, or slightly higher to those with the l/l genotype. In contrast, among subjects with the less efficient 2/3/5 MAOA-uVNTR alleles, those with l/s or s/s genotypes had lower N and higher C domain/facet scores that were lower than their l/l counterparts. The NEO pattern of low N and high C has been reported in a number of studies to reflect high levels of resilience. MAOA-uVNTR genotypes that produce less MAOA protein and 5HTTLPR genotypes that produce less serotonin transporter protein could lead to increased serotonergic function via reduced enzymatic degradation and clearance of released serotonin. If these results are replicated in more diverse samples we would suggest that the MAOA-uVNTR 2/3/5 repeats and the 5HTTLPR s genotypes interact to produce a resilient personality profile. This is one of the few studies showing an interaction between these two widely studied genes affecting a psychologically meaningful and important personality profile. Moreover the potentially plausible mechanism, reduced degradation of serotonin by MAOA and reduced uptake by the transporter in people with less active alleles of both genes may suggest potential targets of intervention.